The purpose of this study was to determine the effect of hepatic disease severities on pharmacokinetics of flow-limited verapamil in dimethylnitrosamine (DMN)-induced cirrhotic rats. Hepatic cirrhotic rats (SD rats, 200∼250 g) were induced by intraperitoneal injection with 1% DMN solution at a dose of 10μg/g by 3 days/week as experimental groups and same dose of saline as control for 4 weeks. The serum verapamil concentrations were quantified at zero, 10 min, 30 min, 1, 2 and 3 hrs after bolus injection of 3 mg/kg of verapamil by a column-switching HPLC method and pharmacokinetic parameters such as Co, MRT, AUC, Vdss, t_{1/2 (β)} and CLp were determined in each group. And then some hepatic tissue was obtained and subjected to analysis of the hepatic 4-hydroxyproline content and were inspected by light microscope after hematoxylin and eosin staining. The serum concentrations and pharmacokinetic parameters such as Co, AUC, MRT and t_{1/2 (β)} were significantly increased (p＜0.01) and Vdss and CLp were significantly decreased (p＜0.01) in hepatic cirrhotic rats according to DMN-treated period. The 4-hydroxyproline content was also gradually increased propertionally to DMN-treated period. The pharmacokinetic parameters of verapamil were seemed to change gradually to depend on the hepatic fibrotic severity. Therefore, we suggested that flow-limited drug as like verapamil dosage adjustment is necessary according to hepatic function severity. (Cancer Prev Res 10, 34-47, 2005)

Keywords: Flow-limited verapamil, Cirrhosis, HPLC, Pharmacokinetic parameter